Details

Autor(en) / Beteiligte

• Li, Yao
• Zhao, Ruifang
• Cheng, Keman
• Zhang, Kaiyue
• Wang, Yazhou
• Zhang, Yinlong
• Li, Yujing
• Liu, Guangna
• Xu, Junchao
• Xu, Jiaqi
• Anderson, Gregory J
• Shi, Jian
• Ren, Lei
• Zhao, Xiao
• Nie, Guangjun

Titel

Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition

Ist Teil von

• ACS nano, 2020-12, Vol.14 (12), p.16698-16711

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.